APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Table 1 APOE receptors

APOE receptors	Isoform-specific binding	APOE lipidation required for receptor binding?	APOE binding related functions
LDLR	Lipidated APOE: APOE2 < <APOE3 = APOE4 [65, 66]	Yes [67,68,69]	Mediates lipoprotein and Aβ clearance [4, 70]
LRP1	Lipidated APOE: APOE2 < APOE3 = APOE4 [71]; Non-lipidated APOE: APOE3 binds immobilized LRP1 recombinant cluster IV with a higher affinity than APOE4 [72]	Likely not required although one study suggests otherwise [67, 72, 73]	Mediates lipoprotein and Aβ clearance [70, 74]; signal transduction [15,16,17]; neurotrophic effect [16, 75,76,77,78,79,80].
VLDLR	Non-lipidated APOE: APOE2 = APOE3 = APOE4 [67]	No [67]	Mediates lipoprotein and Aβ clearance [70, 81], as well as reelin signaling [82,83,84].
APOER2/LRP8	Non-lipidated APOE: APOE2 < <APOE3 = APOE4 [85]	No [85]	Mediates reelin signaling [82,83,84]; regulates intracellular trafficking of synaptic receptors [18].
HSPG	Non-lipidated APOE: APOE2 < APOE3 < APOE4 [86]	No [41, 86]	Mediates lipoprotein and Aβ clearance [4, 70]
TREM2	Both lipidated and non-lipidated APOE: APOE2 = APOE3 = APOE4 [62,63,64]	No [62,63,64]	Mediates microglial phagocytosis of Aβ and damaged neurons [64, 87, 88]; Maintains neurodegenerative phenotype (MGnD) of disease-associated microglia (DAM) [89, 90].

ISSN: 1750-1326